We request five years of continued support for the longitudinal study of cognitively normal persons with two, one, or no copies of the apolipoprotein E (APOE) 4 allele, the major late-onset Alzheimer's disease (AD) susceptibility gene. This study utilizes an extensive battery of brain imaging, fluid biomarker, cognitive, and other measurements. Our program includes a cohort of 35 4 homozygotes, 50 4 heterozygotes, and 75 4 non-carriers to permit detection, tracking, and scientific study of preclinical AD in persons at three levels of risk and set the stage for the accelerated evaluation of preclinical AD treatments. It also includes a cohort of 15 4 carriers and 30 4 non-carriers from the Latino community to help establish the extent to which our findings are relevant to this understudied minority group. Persons in each genetic group were demographically matched and initially late middle-aged; their current age is 67 years (range 49-81). And, all participants have had genome-wide single nucleotide polymorphism (SNP) genotyping. During the proposed funding period participants will have PET measurements of regional cerebral metabolic rates of glucose (CMRgl) and fibrillar amyloid- (A) deposition, an expanded magnetic resonance imaging (MRI) battery, serum and plasma samples drawn and stored, and an extensive battery of clinical, neuropsychological, functional, and behavioral tests every two years. At least half will have longitudinal cerebrospinal fluid (CSF) samples drawn, stored, and assayed every two years. For nearly two decades our overriding goals have been to characterize the biomarker and cognitive measurements associated with preclinical AD and provide a foundation for the accelerated evaluation of promising prevention therapies. With the growing number of participants progressing to mild cognitive impairment (MCI) and dementia due to AD, we will begin to characterize the extent to which different biomarker and cognitive measurements predict subsequent rates of clinical progression. With an expanded arsenal of biomarkers and data analysis tools, we will further characterize the biological processes involved in the predisposition to AD. With our preclinical endophenotypes and complementary datasets, we will help clarify relationships between genetic risk factors and potentially dissociable elements of AD. With an expanded data and sample sharing program, we will provide an accessible worldwide resource to advance the study of preclinical AD. With this foundation of participants, samples, and longitudinal data, we will prepare for the evaluation of an A-modifying agent in cognitively normal APOE 4 carriers and help to advance a new era in AD prevention research.